Prion disease in Indigenous Australians.

BACKGROUND: Indigenous Australians are at increased risk of developing dementia - Alzheimer disease and mixed dementia diagnoses are the most common. While prion diseases have been reported in Indigenous peoples of Papua New Guinea and the United States, the occurrence and phenotype of prion disease in Indigenous Australians is hitherto unreported. AIM: To report the incidence rate and clinical phenotype of Creutzfeldt-Jakob disease (CJD) in Indigenous Australians. METHOD: Crude sporadic CJD (sCJD) incidence rates and indirect age standardisation of all CJD were assessed to calculate the standardised mortality ratio (SMR) of the Indigenous Australian population in comparison to the all-resident Australian population, along with analysis of clinical phenotypes. RESULTS: We report an illustrative case of an Indigenous Australian from regionally remote Western Australia dying from typical 'probable' sCJD 2 months after disease onset, with Australian National CJD Registry (ANCJDR) surveillance overall demonstrating eight Indigenous Australians dying from sCJD (five post-mortem confirmed, three classified as 'probable') with a clinical phenotype similar to non-indigenous people, including median age at death of 61 years (interquartile range IQR = 16 years) and median duration of illness of 3 months (IQR = 1.6 months). Indigenous Australians with sCJD were geographically dispersed throughout Australia. The calculated overall crude annual rate of sCJD in Indigenous Australians compared to the remainder of the Australian population was not significantly different (0-3.87/million for Indigenous Australians; 0.94-1.83/million for non-indigenous). The overall indirect age-standardised CJD mortality ratio for the indigenous population for the years 2006-2018 was 1.49 (95% CI, 0.75-2.98), also not significantly different to the all-resident Australian population. CONCLUSION: CJD occurs in Indigenous Australians with clinical phenotype and occurrence rates similar to non-Indigenous Australians. These findings contrast with a previous report where the incidence rate of CJD in a non-Australian indigenous population was reported to be decreased.

Prion protein "gamma-cleavage": characterizing a novel endoproteolytic processing event.

The cellular prion protein (PrP(C)) is a ubiquitously expressed protein of currently unresolved but potentially diverse function. Of putative relevance to normal biological activity, PrP(C) is recognized to undergo both α- and ß-endoproteolysis, producing the cleavage fragment pairs N1/C1 and N2/C2, respectively. Experimental evidence suggests the likelihood that these processing events serve differing cellular needs. Through the engineering of a C-terminal c-myc tag onto murine PrP(C), as well as the selective use of a far-C-terminal anti-PrP antibody, we have identified a new PrP(C) fragment, nominally 'C3', and elaborating existing nomenclature, 'γ-cleavage' as the responsible proteolysis. Our studies indicate that this novel γ-cleavage event can occur during transit through the secretory pathway after exiting the endoplasmic reticulum, and after PrP(C) has reached the cell surface, by a matrix metalloprotease. We found that C3 is GPI-anchored like other C-terminal and full length PrP(C) species, though it does not localize primarily at the cell surface, and is preferentially cleaved from an unglycosylated substrate. Importantly, we observed that C3 exists in diverse cell types as well as mouse and human brain tissue, and of possible pathogenic significance, γ-cleavage may increase in human prion diseases. Given the likely relevance of PrP(C) processing to both its normal function, and susceptibility to prion disease, the potential importance of this previously underappreciated and overlooked cleavage event warrants further consideration.

Creutzfeldt-Jakob disease surveillance in Australia: update to December 2014.

Nation-wide surveillance of human transmissible spongiform encephalopathies (also known as prion diseases), the most common being Creutzfeldt-Jakob disease, is performed by the Australian National Creutzfeldt-Jakob Disease Registry, based at the University of Melbourne. Prospective surveillance has been undertaken since 1993 and over this dynamic period in transmissible spongiform encephalopathy research and understanding, the unit has evolved and adapted to changes in surveillance practices and requirements concomitant with the emergence of new disease subtypes, improvements in diagnostic capabilities and the overall heightened awareness of prion diseases in the health care setting. In 2014, routine national surveillance continued and this brief report provides an update of the cumulative surveillance data collected by the Australian National Creutzfeldt-Jakob Disease Registry prospectively from 1993 to December 2014, and retrospectively to 1970.

Creutzfeldt-Jakob disease surveillance in Australia: update to December 2015.

Nation-wide surveillance of human transmissible spongiform encephalopathies (also known as prion diseases), the most common being Creutzfeldt-Jakob disease, is performed by the Australian National Creutzfeldt-Jakob Disease Registry, based at the University of Melbourne. Prospective surveillance has been undertaken since 1993 and over this dynamic period in transmissible spongiform encephalopathy research and understanding, the unit has evolved and adapted to changes in surveillance practices and requirements concomitant with the delineation of new disease subtypes, improvements in diagnostic capabilities and the overall heightened awareness of prion diseases in the health care setting. In 2015, routine national surveillance continued and this brief report provides an update of the cumulative surveillance data collected by the Australian National Creutzfeldt-Jakob Disease Registry prospectively from 1993 to December 2015, and retrospectively to 1970.

Creutzfeldt-Jakob disease surveillance in Australia, update to December 2013.

Nation-wide surveillance of transmissible spongiform encephalopathies including Creutzfeldt-Jakob disease, is performed by the Australian National Creutzfeldt-Jakob Disease Registry, based at the University of Melbourne. Surveillance has been undertaken since 1993. Over this dynamic period in transmissible spongiform encephalopathy research and understanding, the unit has evolved and adapted to changes in surveillance practices and requirements, the emergence of new disease subtypes, improvements in diagnostic capabilities and the overall heightened awareness and understanding of Creutzfeldt-Jakob disease and other transmissible spongiform encephalopathies in the health care setting. In 2013, routine surveillance continued and this brief report provides an update of the surveillance data collected by the Australian National Creutzfeldt-Jakob Disease Registry prospectively from 1993 to December 2013, and retrospectively to 1970. The report highlights the recent multi-national collaborative study published that has verified the correlation between surveillance intensity and reported disease incidence.

The prion protein preference of sporadic Creutzfeldt-Jakob disease subtypes.

Sporadic Creutzfeldt-Jakob disease (CJD) is the most prevalent manifestation of the transmissible spongiform encephalopathies or prion diseases affecting humans. The disease encompasses a spectrum of clinical phenotypes that have been correlated with molecular subtypes that are characterized by the molecular mass of the protease-resistant fragment of the disease-related conformation of the prion protein and a polymorphism at codon 129 of the gene encoding the prion protein. A cell-free assay of prion protein misfolding was used to investigate the ability of these sporadic CJD molecular subtypes to propagate using brain-derived sources of the cellular prion protein (PrP(C)). This study confirmed the presence of three distinct sporadic CJD molecular subtypes with PrP(C) substrate requirements that reflected their codon 129 associations in vivo. However, the ability of a sporadic CJD molecular subtype to use a specific PrP(C) substrate was not determined solely by codon 129 as the efficiency of prion propagation was also influenced by the composition of the brain tissue from which the PrP(C) substrate was sourced, thus indicating that nuances in PrP(C) or additional factors may determine sporadic CJD subtype. The results of this study will aid in the design of diagnostic assays that can detect prion disease across the diversity of sporadic CJD subtypes.

Intensity of human prion disease surveillance predicts observed disease incidence.

BACKGROUND: Prospective national screening and surveillance programmes serve a range of public health functions. Objectively determining their adequacy and impact on disease may be problematic for rare disorders. We undertook to assess whether objective measures of disease surveillance intensity could be developed for the rare disorder sporadic Creutzfeldt-Jakob disease (CJD) and whether such measures correlate with disease incidence. METHOD: From 10 countries with national human prion disease surveillance centres, the annual number of suspected prion disease cases notified to each national unit (n=17,610), referrals for cerebrospinal fluid (CSF) 14-3-3 protein diagnostic testing (n=28,780) and the number of suspect cases undergoing diagnostic neuropathological examination (n=4885) from 1993 to 2006 were collected. Age and survey year adjusted incidence rate ratios with 95% CIs were estimated using Poisson regression models to assess risk factors for sporadic, non-sporadic and all prion disease cases. RESULTS: Age and survey year adjusted analysis showed all three surveillance intensity measures (suspected human prion disease notifications, 14-3-3 protein diagnostic test referrals and neuropathological examinations of suspect cases) significantly predicted the incidence of sporadic CJD, non-sporadic CJD and all prion disease. CONCLUSIONS: Routine national surveillance methods adjusted as population rates allow objective determination of surveillance intensity, which correlates positively with reported incidence for human prion disease, especially sporadic CJD, largely independent of national context. The predictive relationship between surveillance intensity and disease incidence should facilitate more rapid delineation of aberrations in disease occurrence and assessment of the adequacy of disease monitoring by national registries.

Surveillance for Creutzfeldt-Jakob disease in Australia: update to December 2012.

Nation-wide surveillance for transmissible spongiform encephalopathies including Creutzfeldt-Jakob disease (CJD) is undertaken by the Australian National Creutzfeldt-Jakob disease Registry (ANCJDR), based at the University of Melbourne. Surveillance has been undertaken since 1993. During this period the unit has evolved and adapted to changes in surveillance practices and requirements, the emergence of new disease subtypes, improvements in diagnostic capabilities and the overall heightened awareness and understanding of CJD and other transmissible spongiform encephalopathies in the health care setting. In 2012, routine surveillance continued. This brief report provides an update on the surveillance data collected by the ANCJDR prospectively from 1993 to December 2012, and retrospectively to 1970. It also highlights the recent release of the revised Australian CJD Infection Control Guidelines.

Surveillance of Creutzfeldt-Jakob disease in Australia: update to December 2011.

The Australian National Creutzfeldt-Jakob disease Registry (ANCJDR) is a Commonwealth Government-funded surveillance unit, responsible for the ascertainment of all cases of human transmissible spongiform encephalopathy (also known as prion diseases) in Australia. Having been in operation for 18 years, the activities of the ANCJDR have evolved and expanded over this timeframe, with the ANCJDR providing clinical, diagnostic and infection control advice and service. This update provides a review of the activities of the ANCJDR during 2011 and analysis of both prospective and retrospective (to 1970) data collected from 1993 to 31 December 2011.

Enhanced geographically restricted surveillance simulates sporadic Creutzfeldt-Jakob disease cluster.

Spatio-temporal clustering of sporadic Creutzfeldt-Jakob disease (sCJD) has been recognized and investigated previously in various global settings including Australia. Generally, despite often extensive investigation, explanations such as point source outbreaks and plausible case-to-case transmission links have not been identified to explain the apparently higher case rates than expected. In the context of national surveillance during the period 1993-2006, an increased number of cases of sCJD were recognized in a circumscribed coastal region of eastern Australia. To assess the significance of this apparent clustering, the Spatial Scan Statistic was used to examine for geographic excess of CJD mortality at spatial and temporal combined, spatial only and temporal only levels. A significant spatial cluster was confirmed, encompassing three contiguous statistical local areas within the state of New South Wales (NSW). Detailed epidemiological analysis did not reveal a plausible cross-over or point source transmission event. Further evaluation prompted the conclusion that vigilant and motivated managing clinicians in this geographically circumscribed area of NSW evinced a sustained higher level of clinical awareness for the broad phenotypic spectrum of CJD with reliable referral of suspect cases for further investigation. In addition, these physicians established and maintained a well-coordinated and active approach to suspect CJD autopsy. This combination of factors translated into a higher intensity of surveillance at approximately twice the rate per population observed in the entire state, culminating in twice the incidence of sCJD at around 2.28 cases/million population/year. The hypothesis that intensity of surveillance for rare disorders can be objectively measured and that this can positively correlate with disease incidence deserves further exploration. It may prove to be an important insight into the varying incidence rates over periods of time within individual nations and between different countries.

Intra-cerebral haemorrhage but not neurodegenerative disease appears over-represented in deaths of Australian cadaveric pituitary hormone recipients.

BACKGROUND AND PURPOSE: Recent scientific reports and epidemiological studies have engendered mounting concerns regarding the potential human-to-human transmissibility of non-prion neurodegenerative and related diseases. This study investigated whether recipients of cadaveric pituitary hormone treatments are at increased risk of death from non-prion neurodegenerative and related diseases. METHODS: A retrospective national cohort study based on death certificates of recipients of the cadaveric pituitary hormone treatments (n = 184) as part of the Australian Human Pituitary Hormone Program (AHPHP; n = 2940) 1967-1985. Standardised mortality ratios (SMR) from non-prion neurodegenerative and other diseases were estimated based on the Australian population. RESULTS: Allowing for potential diagnostic mis-attributions, there was no significant increase in the SMR from non-prion central nervous system (CNS) neurodegenerative disease, especially dementia and/or Alzheimer's disease (0.47; [95% CI: 0.19, 1.12] P = 0.081). The SMR for intra-cerebral haemorrhage, potentially related to cerebral amyloid angiopathy (CAA), was increased (2.77; [95% CI: 1.12-5.75] P = 0.009), although accommodation of possible mis-diagnosis through conflation of this category with other stroke causes of death emphasising likely intra-cranial haemorrhage showed no persisting significant increase in mortality in cadaveric pituitary hormone recipients, including all deaths recorded as due to intra-cranial haemorrhage (1.72; [95% CI: 0.80, 3.26] P = 0.123). CONCLUSION: In the setting of recent evidence strongly supporting the likelihood of brain-to-brain horizontal transmission and subsequent propagation and deposition of abnormally folded proteins associated with non-prion neurodegenerative and related disorders, this study offers further tentative support for deaths directly stemming from transmission of non-prion disease related to cadaveric pituitary hormone treatment. Acknowledging the limitations of the present study, however, ongoing detailed assessments of this potential risk are necessary.

Molecular typing of PrPres in human sporadic CJD brain tissue.

Within the spectrum of sporadic human transmissible spongiform encephalopathies (TSEs), there is considerable diversity of disease phenotypes. At least part of this variation is thought to be on the basis of different "strains" of prions (the infectious agent). Tissue deposition of PrP(res) (the abnormal disease-associated conformation of the prion protein) is considered a hallmark of TSE pathology, and it can be visualized by Western blotting typically as three bands depicting the diglycosylated, monoglycosylated, and unglycosylated species. It is the mobility of the unglycosylated PrP(res), and the relative abundance of the two glycosylated bands, along with the prion protein gene (PRNP) codon 129 genotype, that seem to correlate with distinct clinico-pathological profiles of sporadic Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease surveillance in Australia: update to December 2016.

Nation-wide surveillance of human transmissible spongiform encephalopathies (TSE, also known as prion diseases), the most common being Creutzfeldt-Jakob disease, is performed by the Australian National Creutzfeldt-Jakob disease Registry, based at the University of Melbourne. Prospective surveillance has been undertaken since 1993 and over this dynamic period in transmissible spongiform encephalopathy research and understanding, the unit has evolved and adapted to changes in surveillance practices and requirements concomitant with the delineation of new disease subtypes, improvements in diagnostic capabilities and the overall heightened awareness of prion diseases in the health care setting. In 2016, routine national surveillance continued and this brief report provides an update of the cumulative surveillance data collected by the Australian National Creutzfeldt-Jakob disease Registry prospectively from 1993 to December 2016, and retrospectively to 1970.

Correlative studies support lipid peroxidation is linked to PrP(res) propagation as an early primary pathogenic event in prion disease.

To assess whether heightened oxidative stress plays an early and primary pathogenic role in transmissible spongiform encephalopathies (TSE), we undertook detailed correlative studies using a mouse-adapted model of human disease. The spatio-temporal evolution of the abnormal, protease-resistant isoform of the prion protein (PrP(res)) and neuropathological changes were correlated with the occurrence and type of oxidative stress. Heightened oxidative stress was demonstrated, but restricted to elevated levels of free aldehydic breakdown products of lipid peroxidation, affecting all brain regions to varying extents. The increase in lipid peroxidation was highest over the mid-incubation period, with the onset showing close temporal and general topographical concordance with the first detection of PrP(res) with both pre-empting the typical neuropathological changes of spongiform change, gliosis and neuronal loss. Further, prion propagation over the disease course was assessed using murine bioassay. This revealed that the initial rapid increase in infectivity titres was contemporaneous with the abrupt onset and maximisation of lipid peroxidation. The present results are an important extension to previous studies, showing that heightened oxidative stress in the form of lipid peroxidation is likely to constitute an early primary pathogenic event in TSE, associated temporally with the integral disease processes of prion propagation and PrP(res) formation, and consistent with causal links between these events and subsequent typical neuropathological changes.

Surveillance of Creutzfeldt-Jakob disease in Australia: update to December 2010.

Since the establishment of the Australian National Creutzfeldt-Jakob disease Registry (ANCJDR) its activities have expanded from prospectively investigating additional iatrogenic Creutzfeldt-Jakob disease cases to include: retrospective ascertainment to 1970; provision of expert opinions in the area of infection control management; provide diagnostic testing services for all suspect cases; and maintenance of national and international collaborations in conjunction with routine surveillance responsibilities. An update of the ANCJDR's surveillance activities and outcomes between 1 April and 31 December 2010 is herein presented, including a summation of a recent publication by the ANCJDR. The shorter reporting period is due to a contractual change with the Department of Health and Ageing in 2010, resulting in the reporting timeframe shifting to align with full calendar years.

Surveillance of Creutzfeldt-Jakob disease in Australia: 2010 update.

Surveillance of all human prion diseases in Australia has been the responsibility of the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR) on behalf of the Australian Government Department of Health and Ageing since the Registry's inception in October 1993. The ANCJDR was established in response to the identification of 4 CJD deaths in recipients of human-derived pituitary hormone. The initial brief was to perform focused surveillance for any further iatrogenic cases of CJD; however the scope of surveillance was soon expanded to include all cases of CJD occurring in Australia both prospectively and retrospectively to 1970. The activities of the ANCJDR have evolved from: routine surveillance responsibilities to detailed epidemiological analysis at both national and international levels; expert advice in relation to, and management of, infection control issues; and the provision of a number of tests to aid the diagnosis and classification of CJD in suspect cases. In this brief report, surveillance outcomes are examined with the inclusion of figures from the reporting period of 1 April 2009 to 31 March 2010 and the diagnostic services offered by the ANCJDR are outlined to provide a greater insight into this aspect of the Registry.

Iatrogenic Creutzfeldt-Jakob disease in Australia: time to amend infection control measures for pituitary hormone recipients?

From 1967, the Australian Human Pituitary Hormone Program offered treatment for short stature and infertility using human cadaver-acquired pituitary hormones (human growth hormone [hGH] and human pituitary gonadotrophin [hPG]). The program was suspended in 1985 when a growth-hormone recipient in the United States developed Creutzfeldt-Jakob disease (CJD), an incurable and rapidly progressive neurodegenerative disorder. Since this time, recipients have lived with the significant anxiety that they have an elevated risk of developing CJD. Furthermore, additional CJD infection control measures are required when recipients undergo some types of surgery. As it is 20 years since the last Australian pituitary hormone recipient developed CJD, we evaluated the risk for Australian recipients of developing iatrogenic CJD, and compared Australian data with data from New Zealand and selected other countries who had pituitary hormone programs. Our evaluation indicates that pituitary hormone recipients in Australia have the lowest risk of developing iatrogenic CJD, and that Australia is the only country not to have experienced ongoing CJD-related deaths. Thus, we believe that: in the Australian hGH recipient cohort, the risk of developing CJD is sufficiently low for this cohort to no longer require additional infection control measures in the health care setting; and in the Australian hPG recipient cohort, if another 5 years elapses with no further occurrence of CJD in this group, the hPG recipient cohort could also be considered as not requiring additional infection control measures in the health care setting. These recommendations should not be misunderstood as implying that there is no ongoing risk, but that the risk is acceptably low and generally in keeping with guidelines that stratify the risk.